rs2915959

chr19-38506969-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000540.3(RYR1):c.8816+17T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 1,611,250 control chromosomes in the GnomAD database, including 67,238 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8622 hom., cov: 31)
  • Exomes 𝑓: 0.28 (58616 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -3.46

Genes affected

RYR1 (HGNC:10483): (ryanodine receptor 1) This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 19-38506969-T-A is Benign according to our data. Variant chr19-38506969-T-A is described in ClinVar as [Benign]. Clinvar id is 93303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38506969-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.443 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.8816+17T>A		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.8816+17T>A		intron_variant		5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.8816+17T>A		intron_variant		1		P4
RYR1	ENST00000594335.5	c.2268+17T>A		intron_variant, NMD_transcript_variant		1
RYR1	ENST00000599547.6	c.8816+17T>A		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49396 AN: 151504 Hom.: 8586 Cov.: 31

Gnomad AFR AF: 0.431

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.356

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.458

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.336

GnomAD3 exomes AF: 0.320 AC: 80107 AN: 250066 Hom.: 13753 AF XY: 0.320 AC XY: 43326 AN XY: 135382

Gnomad AFR exome AF: 0.437

Gnomad AMR exome AF: 0.391

Gnomad ASJ exome AF: 0.242

Gnomad EAS exome AF: 0.339

Gnomad SAS exome AF: 0.454

Gnomad FIN exome AF: 0.295

Gnomad NFE exome AF: 0.255

Gnomad OTH exome AF: 0.304

GnomAD4 exome AF: 0.275 AC: 402080 AN: 1459630 Hom.: 58616 Cov.: 38 AF XY: 0.280 AC XY: 203207 AN XY: 726104

Gnomad4 AFR exome AF: 0.433

Gnomad4 AMR exome AF: 0.387

Gnomad4 ASJ exome AF: 0.252

Gnomad4 EAS exome AF: 0.338

Gnomad4 SAS exome AF: 0.444

Gnomad4 FIN exome AF: 0.293

Gnomad4 NFE exome AF: 0.250

Gnomad4 OTH exome AF: 0.293

GnomAD4 genome AF: 0.326 AC: 49493 AN: 151620 Hom.: 8622 Cov.: 31 AF XY: 0.334 AC XY: 24698 AN XY: 74042

Gnomad4 AFR AF: 0.432

Gnomad4 AMR AF: 0.356

Gnomad4 ASJ AF: 0.258

Gnomad4 EAS AF: 0.360

Gnomad4 SAS AF: 0.459

Gnomad4 FIN AF: 0.290

Gnomad4 NFE AF: 0.253

Gnomad4 OTH AF: 0.341

Alfa AF: 0.276 Hom.: 1128

Bravo AF: 0.333

Asia WGS AF: 0.484 AC: 1682 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 06, 2014	- -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Central core myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

RYR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

King Denborough syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

not provided Other:1

not provided, no classification provided

literature only

Leiden Muscular Dystrophy (RYR1)

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	0.074
Dann	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2915959; hg19: chr19-38997609; COSMIC: COSV62099492; COSMIC: COSV62099492;